E1 Immunology Flashcards
P- Selectins are found on _____, and its ligand is ____.
It assists migration into ____
P- Selectins are found on Endothelium, and its ligand is Sialyl Lewis Ag.
It assists migration into Peripheral
P-selectins are activated on endothelium cells by:
Histamine and Thrombin released by mast cells and macrophages
E- Selectins are found on _____, and its ligand is ____.
It assists migration into ____
E- Selectins are found on Endothelium, and its ligand is Sialyl Lewis X Ag
It assists migration into Peripheral
E-Selectins are activated by
Cytokines: TNF and IL-1
Secreted by macrophages and mast cells
L- Selectins are found on _____, and its ligand is ____.
It assists migration into ____
L- Selectins are found on NEUTROPHILS, MONOCYTES, T-CELLS, AND B-CELLS, and its ligand is SIALYL LEWIS X AG.
It assists migration into SECONDARY LYMPH NODES VIA HEV
What type of receptor is LFA-1
What expresses it?
What is its ligand?
Integrin
Neutrophils, monocytes, All T-Cells, Naive B-Cells
(Leukocytes and Lymyphocytes)
ICAM-1 and ICAM-2
What type of receptor is Mac-1
What expresses it?
What is its ligand?
Integrin
Neutrophils, monocytes, dendritic cells (Leukocytes)
ICAM-1 and ICAM-2
What type of receptor is VLA-4
What expresses it?
What is its ligand?
Integrin
Monocytes and all T-Cells
VCAM-1
What type of receptor is Alpha(4)Beta(7)
What expresses it?
What is its ligand?
Integrin
Monocytes, T-Cells, B-Cells
VCAM-1 and MadCAM-1
(mucosal addressin cell adhesion molecule-1)
How is an integrin activated?
- Integrins are activated in all leukocytes when chemokines bind to their receptors
- They bind as they are rolling along endothelial surface
- Induces a conformational change in the extracellular domain
- Conformational change leads to increased affinity
- Bent is low-affinity conformation
- Extended is high-affinity conformation
What are the 4 families of chemokines?
What is the determining feature in each one?
- C Chemokines: Single Cysteine
- CC or ß Chemokines: Two Cysteine residues are adjacent
- CXC or Alpha Chemokines: Cysteine residues are separated by an AA
- CX3C chemokines: Two cysteines are separated by three amino acids
What is CCL2 and its function?
A CC Chemokine
Original Name: MCP-1
Major function: Mixed Leukocyte recruitment in transmigration of leukocytes (Monocytes)
What is CXCL8 and its function?
A CXC Chemokine
Original name IL-8
Function: Neutrophil Recruitment in transmigration of leukocytes
Where do dendritic cells go to present an Ag to a Naive T-cell?
How does it get there?
Lymph Nodes
AFFERENT lymphatic vessels
How is a Naive T-cell activated in the lymph nodes?
Once activated, what does it do?
Dendritic Cell presents an Ag to it
Activated T-Cells will leave the Lymph node via the EFFERENT lymphatic vessel
Where are HEV found?
(High Endothelial Venules)
Only in the Lymph Nodes
Where are P and E selectins found?
Where are their ligands found?
Endothelial surfaces
Leukocytes
Where are L-Selectins found?
Where are their ligands found?
On the Lymphocytes
On the endothelial cell
What is an addressin?
An adhesion molecule found on HEV
Assists in the binding and migration of lymphocytes into lymph nodes
What is CCL19 and its function?
CC Chemokine
Original Name: MIP-3ß
Function: T cell and dendritic cell migration into parafollicular zones of LYMPH NODES
Found on HEV
What is CCL21 and its function?
CC Chemokine
Original Name: SLC
T cell and dendritic cell migration into parafollicular zones of lymph nodes
What prevents T-Cells from leaving the lymph node?
In the blood, S1PR1 receptors are internalized because they bind to the S1P ligands. Once they enter the lymph node, there is no S1P ligand, but the S1PR1 receptors are tied up with the S1P that they were originally bound to.
T-Cells naive or activated cannot leave for hours to days until the S1PR1 receptor resurfaces and recognizes the S1P gradient
What is CCL4 and its function?
CC Chemokine
Original name: MIP-1ß
Function: T-cell, dendritic cell, monocyte, and NK Recruitment
Used in homing
It is also an HIV coreceptor
What is CXCL10 and its function?
A CXC Chemokine
Original Name: IP-10
Function: Effector T-Cell Recruitment
In T-Cell homing
What is CXCL12 and its function?
CXC Chemokine
Original name: SDF-11åß
Function: homing of naïve B cells to LNs
What is CSCL13 and its function?
CXC Chemokine
Original name: BCA-1
Function: B-cell migration into follicles; T follicular helper cell migration into follicles
What are the circulating effector cells in innate immunity?
Neutrophils: Early phagocytosis and killing of microbes
Macrophages: Phagocytosis and killing of microbes; Secretes cytokines and stimulate inflammation
NK Cells: Lysis of cells, activation of Macrophages
What are the circulating effector proteins in innate immunity?
Complement: Killing of microbes, opsonization of microbes, activation of leukocytes
Mannose-binding lectin (collecting): Opsonization of microbes, activation of complement (lectin pathway
C-Reactive Protein (pentraxin): Opsonization of microbes, activation of complement
What cytokines of the innate immune system are involved in inflammation?
TNF, IL-1, Chemokines
What cytokines are involved in resistance to viral infection of the innate immune system?
IFN-a and IFN-ß
What cytokines are involved in Macrophage activation of the innate immune system?
IFN-y
What cytokines are involved in IFN-y production by NK cells and T-cells of the innate immune system?
IL-12
What cytokines are involved in the proliferation of NK cells of the innate immune system?
IL-15
What cytokines are involved in the control of inflammation of the innate immune system?
IL-10 and TGF-ß
What are the steps in PRR-Triggered responses Phagocytes
- Phagocytes use PRR to recognize self from non-self
- Recognition of fMet on prokaryotes
(fMet is not found on eukaryotes)
- Polymorphonuclear cells bind proteins that start with fMet
- Use those protein attached cells to control motility and initiate phagocytosis
What are the roles of TLR’s?
Toll-like receptors
Recognize foreign materials
Also activates inflammation
What are the cell surface TLR’s and what do they recognize?
TL-1-2-4-5- and -6
Recognize extracellular microbes
What TLR’s are found on endosomes and what do they recognize?
TLR -3-7-8- and -9
Nucleic acids
Receptor TLR1: TLR2 Heterodimer
Binds to Lipopeptides and GPI
Found on Monocytes, dendritic cells, eosinophils, basophils, and mast cells
Located on the plasma Membrane
Receptor: TLR2: TLR6 Heterodimer
Binds to Lipoteichoic acid or Zymosan
Found on Monocytes, dendritic cells, eosinophils, basophils, and mast cells
Located on the plasma membrane
Receptor TLR3
Binds to Double-stranded viral RNA
Found on NK Cells
Located on Endosomes
Receptor: TLR4:TLR4 Homodimer
Binds to Lipopolysaccharide
Found on Macrophages, dendritic cells, mast cells, and eosinophils
Located on the plasma membrane
Receptor TLR5
Binds to Flagellin
Found on intestinal epithelium
Located on the plasma membrane
Receptor TLR7
Binds to Single Stranded viral RNA’s
Found in Plasmacytoid dendritic cells, NK cells, eosinophils, and B cells
Located on endosomes
Receptor TLR8
Binds to Single Stranded viral RNAs
Found in NK cells
Located on endosomes
Receptor TLR9
Binds to Unmethlylated CpG-Rich DNA
Found in Plasmacytoid dendritic cells, B Cells, eosinophils, and basophils
Located on endosomes
Receptors TLR10 Homodimer and heterodimers with TLR1 and 2
Binds to: Unknown
Found on Plasmacytoid dendritic cells, basophils, eosinophils, and B cells
Located in: Unknown
What adaptor proteins are associated with TLR3?
TRIF is the only adaptor protein used to activate NF-kB and IRFs transcription factors
NF-kB: Nuclear factor-kB
IRF: INterferon regulatory factors
What adaptor proteins are used by TLR4?
TLR4 uses both MyD88 and TRIF to activate NF-kb and IRFs transcription proteins
What adaptor proteins are used by TLRs 1,2,5,6,7,8 and 9?
TLRs 1,2,5,6,7,8 and 9 us MyD88 to activate transcription factors NF-kB and IRF
What are NLR’s and their functions?
NOD-Like Receptors
Controls the activation of inflammatory responses
Act as scaffolding proteins that signal for NF-kB and MAPk signaling pathways
How is an Inflammasome activated and what pathway does it initiate?
- Activated when NLR recognizes cytosolic PAMPS and DAMPS
- Can be microbial, crystals, or reduced potassium concentrations
- Activates Caspase-1 which lead to the secretion of IL-1ß and IL-18
- Also leads to Pryroptosis:
- Programmed cell death of macrophages and dendritic cells
- Releases inflammatory mediators
- IL-1ß, IL-18, TNF, IL-6, and IL-8
- Releases inflammatory mediators
- Programmed cell death of macrophages and dendritic cells
What is Pyroptosis and its effects?
Programmed cell death of macrophages and dendritic cells
Cell death leads to the release of inflammatory mediators:
IL-1ß
IL-18
TNF
IL-6
IL-8
What are Scavenger Receptors and their functions?
Scavenger Receptors are found on macrophages that mediate recognition and initiate phagocytosis of microorganisms
They recognize PAMPs
They bind negative charges of LPS, Liptoteichoic acid, nucleic acids, ß-glucans and proteins from foreign pathogens
What domain does lectin receptors posses and recognize?
Carbohydrates recognition domain
Carbohydrates: microbial mannose, N-acetylglucosamine, and ß-glucans
NB! Compare: Eukaryotic cell carbohydrates are most often terminated by galactose and sialic acid
What are eukaryotic cell carbohydrates most often terminate by?
Galactose and sialic acid
What are the Lectins functions?
Facilitate phagocytosis of macrophages and dendritic cells, secrete cytokines to initiate adaptive immunity
Soluble mannose-binding lectin (MBL) is involved in complement activation via the lectin pathway
What are the 5 components of inflammation?
- Increased in blood supply to the affected area
- Leads to redness and heat
- Increased capillary permeability
- Leads to leaks from the blood vessels
- Swelling and pain
- Massive influx of neutrophils in the tissues
- Arrival of monocytes and macrophages (16-48 hours)
- Distortion of the homeostasis and loss of function
What is HMGB1?
A DAMP secreted from necrosis.
Activates the NF-kB pathway
RAGE is its receptor
What is Uric Acid?
A DAMP that induces the transcription of NF-kB
What are HSPs?
A DAMP that induces NF-kB pathway
Induce release of inflammatory cytokines: TNF-alpha and IL-1ß
What are defensins?
Where are they found?
What do they do?
Small cationic peptides with a cationic region and a hydrophobic region
Made by epithelial cells of mucosal surfaces and by granule-containing leukocytes
Directly toxic to microbes (bacteria, fungi, and enveloped viruses)
They insert and disrupt their membranes
What are Cathe’licidins?
Where are they found?
What do they do?
Antimicrobial peptides
Found in neutrophils and barrier epithelia of skin, GI, and respiratory
They can be directly toxic to microbes and activate leukocytes
They can also be antiinflammatory by binding to DNA and preventing Inflammasome activation
Are natural killer T-cells part of adaptive or innate immunity?
Innate
KARS vs KIRS
What are they?
What do each do?
What determines if a cell dies
Activating Receptors (Killer cell Ig-like receptor) vs Inhibitory Receptors
Recognizes: Stress molecules (MICA and MICB) vs Class I MHC
KARS: Will lead to protein kinases that will activate proteins to kill the host cell
KIRS: Sufficient binding will lead sparing of the target cell
Insufficient binding will lead to killing of the host cell
Steps of NK cells killing target
- NK cell releases perforins which polymerize and form a hole in the target cell
- Granzymes from NK enter perforin hole and degrade enemy enzyme
- Host cell dies by apoptosis
- Macrophages engulfs and digest dying cell
What is a zymogen?
How does it relate to the complement cascade?
An inactive precursor enzyme
It is altered to become an active protease that will cleave the next complement protein in the cascade
Describe the role of C3 Convertase in the complement pathway
C3 Convertase will cleave C3 to produce C3a and C3b
C3a: Chemoattractant for neutrophils and stimulates inflammation
C3b: Binds to microbial surface as an opsonin to promote phagocytosis
C3 Convertase + C3b = C5 Convertase
Used in the next step of complement
Describe the role of C5 Convertase in the complement pathway
Cleaves C5 to produce C5a and C5b
C5a: is a chemoattractant for neutrophils and also induces changes in the permeability of blood vessels
C5b: Attaches to the bacterial surfaces and initiates the MAC Complex
What role does the MAC complex play in the complement cascade?
Creates a hole in the membrane that leads to bacterial leakage and lysis
How is MAC made in the complement system?
- C6 and C7 bind to C5b to form a complex (C7 is what allows it to bind to the bacterial membrane)
- C8 binds to the complex and inserts itself on to the membrane
- C5bC6C7C8 complex is used to allow the polymerization of 1-16 C9 molecules to form the pore
(The pore is made of C9 molecules that were allowed to be formed because of the C5bC6C7C8 complex)
What allows the activation of the alternative complement pathway?
The creation of C3b via
a. “tickover” of C3 (spontaneous degradation)
b. Positive feedback from the creation of C3 convertase complex with C3bBb and C3 convertase
c. C3b produced from Classical or Lectin Pathway
How is C3b used in the alternative complement pathway?
- C3b binds to Factor B
- Factor B is cleaved into Bb and Ba via Factor D
- C3b binds to Bb and becomes a C3 Convertase
Creates C3bBb Convertase that will cleave more C3 to create positive feedback
** Side note** Properdin binds to the C3bBb convertase to stabilize it
*** Binding of another C3b will create a C5 Convertase
What stabilizes the C3bBb Convertase complex in the alternative pathway?
Properdin
What is the function of MBL in the Lectin complement pathway?
It is the receptor that recognizes the glycoproteins and glycolipids on the cell surfaces of microbes
When it binds, it activates MASP1 and MASP2: Which is similar to the C1r and C1s Components of the Classical Pathway
(Mannose-associated serine proteases)
What is the role of MASP1 and MASP2?
What complement pathway do they belong to?
They are part of the Lectin Complement Pathway
They are mannose associated serine proteases
They cleave C2 and C4 to create C4bC2a.
C4bC2a is a C3 Convertase
What is DAF?
A complement regulatory protein that blocks the interaction between C2:C4b
Also promotes the disassociation of the C3 complex: C4bC2a
What is CR1?
A complement regulatory protein
Promotes the disassociation of the C3 convertase: C4bC2a
(Complement receptor 1 also serves as a cofactor for Factor I)
What is the role of Factor 1?
Uses cofactor CR1
Will prevent the assembly of C3 and C5 convertases
Role of C5a
Recruitment of leukocytes
Change the permeability of blood vessels
(Plays a role in the complement pathway)
Role of C3a
Stimulates inflammation
Recruitment of leukocytes
(Plays a role in the complement pathway)
Role of C3b
Opsinin that is involved in recognition of microbe by phagocyte
Also involved in the creation of multiple C5 convertases
(Plays a role in the complement pathway)
What cells do C3a, C4a, and C5a activate?
Mast Cells, basophils, neutrophils, monocytes, and macrophages
(leukocytes)
What role do mast cells and basophils have in inflammation?
They release vasoactive substances
What role do neutrophils have in inflammation?
They increase chemokinesis, release prostaglandins, and utilize ROS and RNS
What role do monocytes and macrophages have in inflammation
They release IL-1 and IL-6, prostaglandins, and ROS and RNS
What are the inflammatory effects of soluble complement fragments?
Contraction of smooth muscles
Increased permeability of blood vessels
Degranulation of basophils
Chemotaxis, release of NOS and lysosomal enzymes
(All stimulated by C3a, C4a, but mainly C5a)
(**Note C4a hardly does any because their receptors are rarely found)
What are the steps of phagocytosis and the killing of the microbes?
- Complement activation leads to depositions of C3b on the bacterial cell surfaces
- Cr1 on macrophages recognize it and bind to the bacterium
- Endocytosis begins
- Macrophage membranes fuse creating a phagosome with the bacteria inside
- Phagosome fuses with the lysosome to create a phagolysosome
- Contains ROS, NOS, and proteolytic enzymes that will degrade it
What can bacteria express that will prevent the killing of the bacteria in the phagolysosome?
Catalase
Will neutralize the hydrogen peroxide which would have been used by myeloperoxidases to create hydroxide and chlorine that will destroy the cells
What are collectins?
Pattern Recognition Receptors (PRRs) that contain lectin heads
Used in innate immunity
What are Pulmonary Surfactant proteins SP-A and SPD?
What is their role?
Collectins with PRRs
They can act as opsinins (for phagocytosis), inhibit bacterial growth, and activate macrophages
Found in the lungs
What are Filocins?
Plasma proteins that are used in the humoral innate immune system
They are PRRs that recognize carbohydrates:
N-acetylglucosamine and N-acetyl
They will opsonize for phagocyte recognition and activate lectin complement vias MASPs
What induces acute inflammation and promote the expression of IL-6?
TNF and IL-1
What are the shared effects of TNF, IL-6, and IL-1?
Mediate protective systemic effects of inflammation
Induction of fever, acute phase proteins by the liver, and leukocytosis (production of leukocytes)
What are the negative side effects of TNF
Decreased cardiac output
Thrombosis and capillary leak
Metabolic abnormalities due to insulin resistance
All of which can lead to septic shock
What are CRP and SAP?
Acute phase protein s
What can CRP and SAP do?
Recognize and phosphorylcholine and phosphatidylethanolamine respectively
Can activate classical complement pathway by binding to C1q
What are the properties of Abs
(7 of them)
Immunomodulation
Reduce damage to host from an inflammatory response
Organized T-Cell response
Opsonization
Activation of complement (Classical)
Toxin Neutralization
Direct antibody antibacterial activity
What are the chains and domains of the Ab structure?
Light Chain and Heavy Chain
Variable Domain: Ag Binding domain
Constant Domain: Determines the type of Ab
Papain’s function
Cleaves IgG into two Fab fragments and an Fc fragment
Fab Fragments: Fragment ag-binding
Fc: Fragment crystallized
What is the role of pepsin
Proteolysis that breaks IgG into a bivalent fragment ag-binding fragment (F(ab)2) and a degraded peptide fragment
What are the 5 types of heavy chains and their corresponding Ig__?
Mu, delta, gamma, epsilon, and alpha
IgM, IgD, IgG, IgE and IgA
What is the reason that IgM is membrane-bound?
compared to IgG which has a tail region, it has an extra CH4 domain that anchors it to the plasma membrane
In which types of foreign materials is high affinity binding of the ab most crucial?
Toxins and viruses
What is valence and how does it apply to Ab binding?
Valence is how many Ags an Ab can bind to
(I.e. IgG has two binding sites: Therefore, valence =2)
Having two or more binding sites for an Ag can dramatically increase the tightness of binding
What is avidity?
Avidity is the overall strength of binding between Ag-Ab
What are the two factors that avidity is dependent on?
Affinity of the Ab for a SINGLE epitope
AND
Valence fo BOTH Ab and Ag
